Who is this trial for?
This trial was for adults with bladder cancer that had grown into the muscle of the bladder wall, who were not able to receive cisplatin chemotherapy and were planned for surgery to remove the bladder.
People in the trial had:
- Muscle-invasive bladder cancer (MIBC) that had grown into the bladder muscle but had not spread to distant organs (stage T2–T4a N0–1 M0).
- Cisplatin-ineligibility — unable to receive cisplatin chemotherapy due to kidney problems, hearing loss, or poor physical condition, among other reasons.
- A plan for radical cystectomy (surgical removal of the bladder).
What kind of trial is this?
This trial tested a new combination for treating bladder cancer around the time of surgery — both before and after the bladder is removed.
Background: why researchers asked this question
For muscle-invasive bladder cancer, the standard approach is surgery — removing the entire bladder — usually preceded by cisplatin-based chemotherapy. That chemotherapy shrinks the cancer before surgery and kills cells that may have spread beyond what imaging can detect, improving survival.
But many patients with bladder cancer cannot receive cisplatin because of kidney problems (cisplatin is filtered through the kidneys and can be toxic) or other health issues. For these patients, the previous standard was surgery alone — without the benefit of any pre-operative treatment. Outcomes were poor.
Enfortumab vedotin (EV) — an ADC targeting the Nectin-4 protein on bladder cancer cells — and pembrolizumab (a PD-1 immunotherapy) had already proven highly effective in advanced, metastatic bladder cancer. Researchers asked: could giving them around surgery help cisplatin-ineligible patients, replacing cisplatin altogether?
The trial: what was tested and how
EV-303 (also called KEYNOTE-905) enrolled 344 people with muscle-invasive bladder cancer who were cisplatin-ineligible. They were randomly assigned 1:1 to:
- EV + pembrolizumab + surgery: 3 treatment cycles before surgery, then surgery, then 6 more EV cycles and pembrolizumab continued for up to 17 total cycles.
- Surgery alone: the previous standard of care for cisplatin-ineligible patients — no treatment before or after surgery.
The main measure was event-free survival (EFS) — how long before the cancer came back, couldn’t be removed by surgery, or the person died. Key secondary measures were overall survival and pathological complete response (pCR) — whether any live cancer cells remained in the removed bladder.
A note before the results
Harry first noticed some blood-tinged urine a few months ago. He brought it up with his family doctor and was able to meet a urologist, who found his bladder tumor. The biopsy showed the tumor was already invading the bladder muscle. The problem is that Harry has a history of working with loud machines, with significant hearing loss at a relatively young age of 68. Furthermore, he has had diabetes for about 10 years and has some impaired kidney function. He just retired last year and is still active with his local gardening club, and walks his dogs every day. His urologist is happy to do surgery, but Harry would be a difficult patient for our traditional chemotherapy, given his hearing loss and his kidney disease. This trial opens up a great new option for Harry.
Results: what they found
EV + pembrolizumab around surgery was far better than surgery alone across every major measure — including both cancer-free time and survival.
EV + pembrolizumab vs surgery alone — at 2 years
Nearly twice as many people were alive and cancer-free at 2 years with the EV combination — a 60% lower risk of the cancer returning or of dying (HR 0.40).
More people were alive at 2 years with the combination — a 50% lower risk of dying (HR 0.50). This is a remarkable survival benefit in a disease with historically poor outcomes for this group.
Over half the patients who received EV + pembrolizumab had no live cancer cells found in the removed bladder — compared to fewer than 1 in 10 in the surgery-alone group. Complete pathological response is associated with better long-term outcomes.
Side effects were substantial. Grade 3 or higher adverse events occurred in 71.3% of the EV + pembrolizumab group versus 45.9% in the surgery-alone group. Common EV-related side effects included skin reactions, fatigue, and peripheral neuropathy (numbness or tingling in hands and feet). The combination also includes the immune-related side effects of pembrolizumab.
How to put the side effects in context
While the side effect rate is high, the alternative for cisplatin-ineligible patients was surgery alone — and many still experienced surgical complications. The EV + pembrolizumab group had a far better chance of being alive and cancer-free at 2 years, which is the key comparison. Side effects from EV + pembrolizumab are manageable with careful monitoring and dose adjustments. Your team will watch closely for neuropathy and skin reactions in particular.
The bottom line
For cisplatin-ineligible patients with muscle-invasive bladder cancer, enfortumab vedotin plus pembrolizumab given around surgery (before and after) dramatically outperformed surgery alone — doubling the 2-year event-free survival rate and improving overall survival by 16 percentage points. The pathological complete response rate was nearly seven times higher. This trial has fundamentally changed the perioperative options for this population.
What this could mean for you
- This is specifically for cisplatin-ineligible patients. If you can receive cisplatin, other standards may apply; discuss with your oncologist which approach fits your situation.
- Timing matters. Treatment starts before surgery (neoadjuvant), then continues after. The full benefit required both the pre- and post-surgery treatments.
- Side effects are real but manageable. Skin reactions and neuropathy are common; regular monitoring is essential. Your team will adjust doses as needed.
- High pCR is a promising sign. Having no live cancer in the removed bladder is strongly associated with better long-term outcomes.
An oncologist’s perspective
Harry is lucky to have the option of enfortumab vedotin (EV) and pembrolizumab, even though EV is still a pretty tough chemotherapy for many people as they get older. EV-pembrolizumab is now not only standard of care for cisplatin-ineligible patients, but is now also standard of care in first-line metastatic bladder cancer, and is likely replacing cisplatin-based chemotherapy as well for healthier patients. This is a new era of antibody-drug conjugates, and bladder cancer is a great example of how we are replacing traditional chemotherapy with these new drugs that bring the toxin to the cancer cell directly, increasing efficiency and potency without increasing toxicity.
Questions & comments
Have a question about this trial? Ask below. Questions are read and answered by the site. We can’t give personal medical advice, but we’re glad to explain the research more clearly.